chrX-71616547-T-G

Variant names:

• chrX-71616547-T-G
• rs766079896
• NM_001504.2:c.925A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001504.2(CXCR3):​c.925A>C​(p.Met309Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: CXCR3 NM_001504.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.27

Genes affected

CXCR3 (HGNC:4540): (C-X-C motif chemokine receptor 3) This gene encodes a G protein-coupled receptor with selectivity for three chemokines, termed CXCL9/Mig (monokine induced by interferon-g), CXCL10/IP10 (interferon-g-inducible 10 kDa protein) and CXCL11/I-TAC (interferon-inducible T cell a-chemoattractant). Binding of chemokines to this protein induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the isoforms (CXCR3-B) shows high affinity binding to chemokine, CXCL4/PF4 (PMID:12782716). [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102222204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXCR3	NM_001504.2	c.925A>C	p.Met309Leu	missense_variant	Exon 2 of 2	ENST00000373693.4	NP_001495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXCR3	ENST00000373693.4	c.925A>C	p.Met309Leu	missense_variant	Exon 2 of 2	1	NM_001504.2	ENSP00000362797.3
CXCR3	ENST00000373691.4	c.1066A>C	p.Met356Leu	missense_variant	Exon 2 of 2	1		ENSP00000362795.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097126 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 362564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1066A>C (p.M356L) alteration is located in exon 2 (coding exon 1) of the CXCR3 gene. This alteration results from a A to C substitution at nucleotide position 1066, causing the methionine (M) at amino acid position 356 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.1
DANN	Benign	0.72
DEOGEN2	Benign	0.10	.;T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	.;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.062
Sift	Benign	0.80	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0090	B;B
Vest4		0.19
MutPred		0.43		.;Loss of phosphorylation at Y308 (P = 0.2034);
MVP		0.89
MPC		0.68
ClinPred		0.066	T
GERP RS		2.7
Varity_R		0.084
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs766079896; hg19: chrX-70836397;